3&#34;-Phenyldispiro[1,3-dioxolane-2,4&#39;-cyclohexane-1&#39;,1&#34;-(3&#34;H)-isobenzofuran]

ABSTRACT

Spiro[cyclohexane-1,1&#39;(3&#39;H)-isobenzofuran]s are useful as anti-depressants, tranquilizers, analgesics and anticonvulsants.

This is a division of application Ser. No. 073,055 filed Sept. 6, 1979now U.S. Pat. No. 4,263,317.

DESCRIPTION OF THE INVENTION

The present invention relates to novelspiro[cyclohexane-1,1'(3'H)-isobenzofuran]s of the formula ##STR1##wherein R₁ is hydrogen; R₂ is NR₅ R₆ wherein R₅ is hydrogen, loweralkyl;##STR2## R₆ is hydrogen or loweralkyl; R₃ is hydrogen, loweralkyl orcycloalkyl having 3 to 7 carbon atoms, inclusive, ##STR3## wherein X ishydrogen, halogen or loweralkyl; R₄ is hydrogen, loweralkyl or hydroxy;R₃ and R₄ taken together with the carbon atom to which they are attachedform a carbonyl group; the geometrical isomers and optical antipodesthereof and the pharmaceutically acceptable salts thereof wherein R₅ isnot the ##STR4## group, which compounds exhibit antidepressant,tranquilizer, analgesic and anticonvulsant activity.

Preferred isobenzofurans of the present invention are those wherein R₃is ##STR5## and R₄ is hydrogen. Particularly preferred compounds arethose wherein R₂ is NR₅ R₆ wherein R₅ and R₆ are each independentlyhydrogen or loweralkyl and those wherein R₆ is hydrogen or loweralkyland R₅ is ##STR6##

The present invention also relates to compounds of the formulas ##STR7##wherein R₅, R₆ and R₉ are loweralkyl; and the geometric isomers andoptical antipodes thereof ##STR8## wherein R₃ is loweralkyl or ##STR9##wherein X is hydrogen, halogen or loweralkyl; R₅, R₆ and R₇ areloweralkyl; and the geometrical isomers and optical antipodes thereof,which compounds are useful as intermediates for the preparation ofisobenzofurans of Formula I.

As used throughout the specification and appended claims, the term"alkyl" denotes a straight or branched saturated hydrocarbon radical.Examples of alkyl groups are methyl, ethyl, isopropyl, butyl, pentyl andso forth. The term "cycloalkyl" denotes a saturated hydrocarbon grouppossessing at least one carbocyclic ring and having from 3 to 7 carbonatoms in the ring. Examples of cycloalkyl groups are cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. The term"alkanol" denotes a compound derived by coupling an alkyl group andhydroxyl radical. The term "lower" refers to the numerical range of 1 to6.

In the formulas presented herein, substituents attached to thecyclohexane ring system may be in either the cis- ortrans-configuration, i.e., the substituents may be, respectively, on thesame side or on opposite sides of the average plane of the six-memberring. For example, the substituent R₂ attached to the 4-position of thecyclohexane ring may be in either the cis- or trans- configuration withrespect to the spatial configuration of the C-1 ether bond. Thegeometrical isomerism of the compounds of the present invention is showngraphically in the reaction schemes. For example, the compound offormula V (Reaction Scheme A) exists in the cis-configuration, i.e., theNR₅ R₆ and ether substituents being above the average plane of thecyclohexane ring as illustrated by the heavy lines ( ) and thecorresponding compound of formula XXXVI (Reaction Scheme D) exists inthe trans-configuration, i.e., the NR₅ R₆ substituent being below theaverage plane of the cyclohexane ring as illustrated by the broken line(- - - -) and the ether substituted being above the average plane of thering. A light line (--) indicates the substituent may be either above orbelow the average plane of the cyclohexane ring.

The isobenzofurans of the present invention lack an element of symmetryand exist as optical antipodes and in the racemic forms thereof.Optically active isobenzofurans may be prepared from optically activeprecursors. When optically inactive precursors are employed, opticallyactive isobenzofurans may be prepared by standard resolution techniqueswell-known in the art utilizing optically active acids such as, forexample, d-camphorsulfonic acid and 1-tartaric acid.

The novel spiro[cyclohexane-1,1'(3'H)-isobenzofuran]s of the presentinvention and the intermediates thereto are prepared by the sequence ofreactions depicted in Reactions Schemes A to D. To preparespiro[cyclohexane-1,1'(3'H)-isobenzofuran]s of the cis-series, forexample, a 2-bromobenzhydrylloweralkylether of formula II (R₇ isloweralkyl), the synthesis of which is described by V. J. Bauer, et al.,in J. Med. Chem., 19, 1315 (1976), is converted to its lithio derivativeand condensed with a 4-diloweralkylaminocyclohexanone of formula III (R₅and R₆ are loweralkyl) to form the cyclohexanol of formula IV (R₅, R₆and R₇ are loweralkyl) which is cyclized to the cis-isobenzofuran V (R₅and R₆ are loweralkyl) as illustrated in Reaction Scheme A.

The lithio derivative is formed by treating the bromo compound IIdissolved or suspended in an ethereal solvent such as diethylether,dimethoxyethane, dioxane, tetrahydrofuran or the like, with aloweralkyllithium such as methyllithium, ethyllithium, n-butyllithium orthe like in an inert hydrocarbon solvent such as pentane, hexane,heptane or the like. n-Butyllithium in hexane is preferred as istetrahydrofuran as the ethereal solvent.

The condensation is conveniently carried out without isolation of thepreformed lithio derivative at an initial reaction temperature of about-20° to -70° C., a range of about -40° to -50° C. being preferred, and afinal reaction temperature of about -90° to 20° C., a range of about-70° to 0° C. being preferred.

The cyclization is accomplished by means of a mineral or organic acid.Suitable mineral acids include hydrochloric acid, hydrobromic acid,sulfuric acid and the like. Suitable organic acids includetrifluoroacetic acid, methanesulfonic acid, para-toluenesulfonic acidand the like. Mineral acids are preferred. Hydrochloric acid is mostpreferred. The reaction may be preformed in a diluent such as aceticacid, or an inert solvent such as benzene or toluene when an organicacid is employed.

The subsequent modification of the diloweralkylamino substituent of theisobenzofuran V is affected by dealkylation of the tertiary amino groupof V to the secondary amino substituted derivative VIII (R₆ isloweralkyl) followed by alkylation to the fluorobenzoylpropyl compound X(R₆ is loweralkyl). The dealkylation is carried out in 2 steps bymethods well known in the art. In the first step, V is treated with aloweralkylhaloorthoformate or phenylhaloorthoformate of formula VI (R₈is loweralkyl or phenyl and Hal is halogen) in a halocarbon solvent suchas dichloromethane, chloroform or the like, in the presense or absenseof an acid scavenger to form the carbamate VII (R₈ is loweralkyl orphenyl and R₆ is loweralkyl). Suitable acid scavengers include alkalimetal carbonates and bicarbonates, for example, sodoium bicarbonate,potassium carbonate and the like.

In the second step, the resulting carbamate VII is hydrolyzed by analkali metal hydroxide such as lithium, sodium or potassium hydroxide,in a loweralkanol solvent such as methanol, ethanol or propanol atelevated temperatures, preferably at the reflux temperature of thereaction mixture.

The alkylation is accomplished by treating the secondary amine VIII witha 4-halo-p-fluorobutyrophenone of formula IX (Hal is halogen) or theethylene ketal derivative thereof in polar aprotic solvent in thepresence of an acid scavenger. Among suitable polar aprotic solventsthere may be mentioned dimethylacetamide, dimethylformamide,hexamethylphosphoramide and the like. Among suitable acid scavengersthere may be mentioned alkali metal carbonates and bicarbonates such assodium and potassium carbonate and sodium and potassium bicarbonate. Areaction medium comprising sodium bicarbonate or potassium carbonate indimethylformamide is preferred. While the reaction temperature is notnarrowly critical, it is preferred to carry out the alkylation at atemperature within the range of about 60°-120° C., a temperature ofabout 90° C. being most preferred.

To promote the alkylation, particularly when a chloride is employed asthe alkylating agent, it is desirable to use a promoter such as analkali metal iodide. Lithium, sodium or potassium iodide may beemployed. Potassium iodide is preferred.

When the ethylene ketal of IX is used as the alkylating agent, theethylene ketal of X is obtained. To convert the cyclic ketal to thecarbonyl group, X is hydrolyzed under aqueous acidic conditions, knownper se. Appropriate conditions comprise mineral acids, for example,hydrochloric acid, cosolvents, for example, methanol or ethanol and anelevated reaction temperature, for example, the reflux temperature ofthe reaction medium.

The isobenzofuran V also serves as a precursor for the synthesis of3'-loweralkyl substituted compounds of formula XIII (R₄, R₅ and R₆ areloweralkyl). To introduce the 3'-loweralkyl substituent, V is convertedto its 3'-lithio derivative by the process used for the preparation ofthe lithio derivative of II. The lithio derivative so obtained is thenalkylated with a loweralkyl halide of formula XI (R₄ is loweralkyl) ordiloweralkylsulfate of formula XII (R₄ is loweralkyl). The alkylationproceeds conveniently in an ethereal solvent such as diethylether,dimethoxyethane, dioxane, tetrahydrofuran or the like. Tetrahydrofuranis preferred. The reaction temperature is not narrowly critical.However, it is preferred to perform the alkylation at a reducedtemperature within the range of about -80° to 0° C., a reducedtemperature of about -50° C. being most preferred.

Spiro[cyclohexane-1,1'(3'H)-isobenzofuran]s of the cis-series are alsoprepared, as illustrated in Reaction Scheme B, starting from a2-(2-bromophenyl)-4,4-diloweralkyloxazoline of formula XIV (R₉ isloweralkyl), the synthesis of which is reported by V. J. Bauer, et al.,in J. Med. Chem., 19, 1315 (1976). In this sequence, the lithioderivative of the bromophenyloxazoline XIV is formed and condensed witha diloweralkylcyclohexanone of formula III (R₅ and R₆ are loweralkyl) byprocesses substantially similar to those used for the formation of thelithio derivatives of bromodiphenylmethane II and the condensation of IIto the isobenzofuran V via ether IV to afford the cyclohexanol XV (R₅,R₆ and R₉ are loweralkyl), which is cleaved with concomitant cyclizationto the isobenzofuran-3-one XVI (R₅ and R₆ are loweralkyl).

The cleavage of the masked carboxylic acid group of XV, i.e., theoxazoline moiety, is conveniently accomplished by methods known in theart. For example, aqueous acids such as hydrobromic acid, hydrochloricacid and the like may be employed. Hydrochloric acid is preferred. Thecleavage proceeds readily at the reflux temperature of the reactionmixture, although lower temperatures may also be employed to affectlactone formation.

Continuing the sequence, the isobenzofuran-3-one XVI is condensed withan organometallic reagent of the formula XVII (M is Li or MgHal whereinHal is chloride, bromide or iodide and X is hydrogen, halogen orloweralkyl) to form the isobenzofuranol of formula XVIII (R₅ and R₆ areloweralkyl and X is as above) which is reductively cleaved to the diolXIX (R₅, R₆ and X are as above) and cyclized to the isobenzofuran XX (R₅and R₆ are as above). The organometallic condensation is performed byart known methods employing, for example, reagents such as phenyllithiumin hydrocarbon or ethereal solvents or mixtures thereof, at reducedtemperatures within the range of about -50° to -10° C. or tolyl- orhalophenylmagnesium bromides in ethereal solvents at a slightly elevatedtemperature near the reflux temperature of the reaction medium.

The reductive cleavage is also performed by art known methods using, forexample, an alkali metal aluminum hydride such as lithium aluminumhydride, in an ethereal solvent such as tetrahydrofuran at a moderatetemperature of about 40°-80° C.

The cyclization of XIX to XX is accomplished by methods known per seinvolving treatment with mineral acids such as, for example, hydrobromicor hydrochloric acid. A cosolvent such as acetic acid may be used tofacilitate the reaction.

Alternatively, the isobenzofuranol XVIII is converted directly to theisobenzofuran XX by means of acidic reducing agents such as formic acid.

The isobenzofuran-3'-one XVI is also condensed with aloweralkylorganometallic of formula XXI (R₃ is loweralkyl and M is Li orMgHal wherein Hal is chloride, bromide or iodide) to yield theisobenzofuranol XXII (R₃, R₅ and R₆ are loweralkyl) which is reductivelycleaved to the diol XXIII (R₃, R₅ and R₆ are as above) and cyclized tothe isobenzofuran XXIV (R₃, R₅ and R₆ are as above). This sequence iscarried out by processes substantially similar to those employed for thetransformation of XVI to XX via XVIII and XIX.

The isobenzofuran-3'-one XVI is reduced to the 3'-unsubstitutedisobenzofuran XXV (R₅ and R₆ are loweralkyl) by means of diborane in anethereal solvent such as tetrahydrofuran at moderate temperatures up tothe reflux temperature of the reaction medium.

By employing processes analogous to those used for the conversion of Vto X and V to XIII (Reaction Scheme A), various N- and 3'-substitutedisobenzofurans may be prepared from XX, XXIV and XXV.

In another aspect of the invention, illustrated in Reaction Scheme C,the lithio derivative of a 2-bromobenzhydryl loweralkyl ether of formulaII is prepared as hereinbeforedescribed and is condensed with1,4'-dioxaspiro[4.5]decan-8-one (XXVI) by a process analogous to thatutilized for the conversion of II to V (Reaction Scheme A) to afford theisobenzofuran XXVII, the ethylene ketal protecting group of which iscleaved by art recognized means such as hydrochloric acid in methanol atroom temperature to afford the cyclohexanone XXVIII. Utilizing thecyclohexanone XXVIII so obtained, the aminioisobenzofuran XXX isprepared by metal hydride reduction of the oxime derivative XXIX, bothoxime formation and metal hydride reduction being accomplished byconventional methods, the latter involving the use of lithium aluminumhydride in tetrahydrofuran at elevated reaction temperatures.

Similarly, the methoximinoisobenzofuran XXXI is prepared by conventionalmethods and is reduced to the 3'-cyclohexyl-4-aminosiobenzofuran XXXIIby hydrogen in the presence of a hydrogenation catalyst such asplatinum, palladium, rubidium, ruthenium or the like, free or absorpedon a solid support such as carbon, silica and the like, at from about 1to about 10 atomspheres pressure.

Acetic acid is generally used as the hydrogenation solvent, althoughother solvents, for example, alkanols such as methanol, ethanol and thelike are also applicable. In acetic acid, the hydrogenation progressesat a satisfactory rate at room temperature. Increased reactiontemperatures may be employed with other solvents.

As depicted in Reaction Scheme D, to gain entry into thespiro]cyclohexane-1,1'(3'H)-isobenzofuran]s of the trans-series,benzanilide (XXXIII) is condensed with III to afford a mixture ofcis-isobenzofuran-3-one XVI (Reaction Scheme B) and the correspondingtrans-isomer XXXIV (R₅ and R₆ are loweralkyl) which is separated intoits component isomers. The trans-isobenzofuran XXXIV is carried throughthe sequence XXXV to XL by employing procedures hereinbefore describedin Reaction Schemes A and B to obtain the desired N- and 3-substitutedproducts.

The condensation is accomplished in a manner analogous to the conversionof II to IV (Reaction Scheme A), XIV to XV (Reaction Scheme B) and II toXXVII (Reaction Scheme C) by forming the dilithio derivative ofbenzanilide (XXXIII) and coupling it with cyclohexanone III.

The separation is readily accomplished by fraction crystallization ofhydrohalide salt, such as the hydrobromide or hydrochloride, of themixture of basic isomers from an appropriate solvent such as methanoland 2-propanol. ##STR10##

The utility of the compounds of the present invention in the treatmentof depression in mammals is demonstrated by their ability to inhibittetrabenazine induced depression in mice [International Journal ofNeuropharmacology, 8, 73 (1969)], a standard assay for usefulantidepressant properties. Thus, for instance, an intraperitoneal doseof 3.7 mg/kg of body weight and an oral dose of 9.4 mg/kg of body weightofcis-4-dimethylamino-3'-phenylspiro[cyclohexane-1,1'(3'H)-isobenzofuran]demonstrate a 50% inhibition of ptosis of tetrabenazine-induceddepression in mice. Also, an oral dose of 8.4 mg/kg of body weight ofcis-4-dimethylamino-3'-(4-fluorophenyl)spiro[cyclohexane-1,1'(3'H)-isobenzofuran]and an intraperitoneal dose of 2.0 mg/kg of body weight of4-methylamino-3'-phenylspiro[cyclohexane-1,1'(3'H)-isobenzofuran]hydrochloridedemonstrate a similar inhibition in this assay. These data indicate thatthe compounds of the present invention would be useful asantidepressants in mammals when administered in amounts ranging from0.01 to 100 mg/kg of body weight per day.

Compounds of the present invention are also useful as anti-convulsantagents for mammals, as determined by Woodbury, L. A. and Davenport, V.D. [Arch. Int. Pharmacodynam, 92, pp 97-107 (1952)]. For example,cis-4-dimethylamino-3'-phenylspiro[cyclohexane-1,1'(3'H)-isobenzofuran],cis-4-dimethylamino-3'-(4-fluorophenyl)spiro[cyclohexane-1,1'(3'H)-isobenzofuran],cis-3'-(4-chlorophenyl)-4-dimethylaminospiro[cyclohexane-1,1'(3'H)-isobenzofuran]hydrochloride,cis-4-dimethylamino-3'-(4-methylphenyl)spiro[cyclohexane-1,1'(3'H)-isobenzofuran]hydrochlorideandtrans-4-methylamino-3'-phenylspiro[cyclohexane-1,1'(3'H)-isobenzofuran]at an intraperitoneal dose of 21.9, 14.1, 21.1, 32.2 and 25.0 mg/kg ofbody weight, respectively, produce a 50% protection from the effect ofsupramazimal electroshock. These data illustrate that compounds of thepresent invention are useful in treating convulsions in mammals whenadministered in amounts ranging from about 0.01 to about 150 mg/kg ofbody weight per day.

Compounds of the present invention are further useful as analgesics dueto their ability to alleviate pain in mammals, as demonstrated in thephenyl-2-quinone writhing assay in mice, a standard assay for analgesia[Proc. Soc. Exptl. Biol. Med., 95, 729 (1957)]. Thus, for example, asubcutaneous dose of 35.9 and 30.4 mg/kg of body weight of4-amino-3'-phenylspiro[cyclohexane-1,1'(3'H)-isobenzofuran]hydrochlorideand4-amino-3'-cyclohexylspiro[cyclohexane-1,1'(3'H)-isobenzofuran]hydrochloride,respectively, demonstrate a 50% inhibition of writhing produced in thisassay. At a subcutaneous dose of 25 mg/kg of body weight,cis-4-methylamino-3'-phenylspiro[cyclohexane-1,1'(3'H)-isobenzofuran]hydrochloride,cis-4-dimethylamino-3'(4-fluorophenyl)spiro[cyclohexane-1,1'(3'H)isobenzofuran]andtrans-4-methylamino-3'-phenylspiro[cyclohexane-1,1'(3'H)-isobenzofuran]hydrochloridedemonstrate a 57%, 69% and 50%, respectively, inhibition of writhingproduced in the assay. Also at a subcutaneous dose of 20 mg/kg of bodyweightcis-3'-(4-chlorophenyl)-4-dimethylaminospiro[cyclohexane-1,1'(3'H)-isobenzofuran]demonstrates a 79% inhibition of writhing. These data illustrate thatcompounds of this invention are useful for alleviating pain in mammalswhen administered in amounts ranging from about 0.01 to about 100 mg/kgof body weight per day .

Additionally, the compounds of the present invention are useful astranquilizers as demonstrated by their ability to antagonize thetoxicity of amphetamine in aggregated situations in mice [J. Pharmacol.Exp. Therap. 87, 2146 (1946)]. Thus at an intraperitoneal dose of 20mg/kg of body weight,trans-4-{N-[3-(4-fluorobenzoyl)propyloyl]-N-methyl}amino-3'-phenylspiro[cyclohexane-1,1'(3'H)-isobenzofuran]oxalate and cis-4-{N-[3-(4-fluorobenzoyl)prop-1-yl]-N-methyl}amino-3'(2-methylphenyl)spiro[cyclohexane-1,1'-(3'H)-isobenzofuran]hydrochloride antagonize amphetamines toxicity in 90 and 80% of themice, respectively. These data illustrate that the compounds of theinvention are useful as tranquilizers in mammals when administered inamounts ranging from about 0.01 to about 100 mg/kg of body weight.

Other compounds of the invention include:

4-diethylaminospiro[cyclohexane-1,1'(3'H)-isobenzofuran];

4-diisopropylamino-3'-(3-ethylphenyl)spiro[cyclohexane-1,1'(3'H)-isobenzofuran];

4-amino-3'-cycloproylspiro[cyclohexane-1,1'(3'H)-isobenzofuran];

3'-cyclopropyl-4-dimethylaminospiro[cyclohexane-1,1'-(3'H)-isobenzofuran];

4-diisopropylamino-3'-(2-ethylphenyl)spiro[cyclohexane-1,1'(3'H)-isobenzofuran];and

4-diethylamino-3'-(4-isopropylphenyl)spiro[cyclohexane-1,1'(3'H)-isobenzofuran].

Effective quantities of the compounds of the invention may beadministered to a patient by any one of various methods, for example,orally as in capsules or tablets, parenterally in the form of sterilesolutions or suspensions, and in some cases intravenously in the form ofsterile solutions. The free base final products, while effectivethemselves, may be formulated and administered in the form of theirpharmaceutically acceptable addition salts for purposes of stability,convenience of crystallization, increased solubility and the like.

The active compounds of the present invention may be orallyadministered, for example, with an inert diluent or with an ediblecarrier, or they may be enclosed in gelatin capsules, or they may becompressed into tablets. For the purpose of oral therapeuticadministration, the active compounds of the invention may beincorporated with excipients and used in the form of tablets, troches,capsules, elixirs, suspensions, syrups, wafers, chewing gum and thelike. These preparations should contain at least 0.5% of activecompound, but may be varied depending upon the particular form and mayconveniently be between 4% to about 70% of the weight of the unit. Theamount of active compound in such compositions is such that a suitabledosage will be obtained. Preferred compositions and preparationsaccording to the present invention are prepared so that an oral dosageunit form contains between 1.0-300 milligrams of active compound.

The tablets, pills, capsules, troches and the like may also contain thefollowing ingredients: a binder such as microcrystalline cellulose, gumtragacanth or gelatin; an excipient such as starch or lactose, adisintegrating agent such as alginic acid, Primogel, corn starch and thelike; a lubricant such as magnesium stearate or Sterotex; a glidant suchas colloidal silicon dioxide; and a sweetening agent such as sucrose orsaccharin may be added or a flavoring agent such as peppermint, methylsalicylate, or orange flavoring. When the dosage unit form is a capsule,it may contain, in addition to materials of the above type, a liquidcarrier such as a fatty oil. Other dosage unit forms may contain othervarious materials which modify the physical form of the dosage unit, forexample, as coatings. Thus, tablets or pills may be coated with sugar,shellac, or other enteric coating agents. A syrup may contain, inaddition to the active compounds, sucrose as a sweetenting agent, andcertain preservatives, dyes and colorings and flavors. Materials used inpreparing these various compositions should be pharmaceutically pure andnon-toxic in the amounts used.

For the purposes of parenteral therapeutic administration, the activecompounds of the invention may be incorporated into a solution orsuspension. These preparations should contain at least 0.1% of activecompound, but may be varied to be between 0.5 and about 50% of theweight thereof. The amount of active compounds in such compositions issuch that a suitable dosage will be obtained. Preferred compositions andpreparations according to the present invention are prepared so that aparenteral dosage unit contains between 0.5 to 100 milligrams of activecompound.

The solutions or suspensions may also include the following components:a sterile diluent such as water for injection, saline solution, fixedoils, polyethylene glycols, glycerine, propylene glycol or othersynthetic solvents; antibacterial agents such as benzyl alcohol ormethyl paraben; antioxidants such as ascorbic acid or sodium bisulfite;chelating agents such as ethylene diaminetetraacetic acid; buffers suchas acetates, citrates or phosphates and agents for the adjustment oftonicity such as sodium chloride or dextrose. The parenteral preparationcan be enclosed in ampules, disposable syringes or multiple dose vialsmade of glass or plastic.

The following Examples are for illustrative purposes only and are not tobe construed as limiting the invention.

EXAMPLE 1cis-4-Dimethylamino-3'-phenylspiro[cyclohexane-1,1'(3'H)-isobenzofuran]

A solution of 3.4 g ofcis-4-dimethylamino-1-{2-[α-methoxy-(phenylmethyl)]phenyl}cyclohexanol,19 ml of acetic acid and 3.7 ml of hydrochloric acid is heated underreflux for 10 minutes, cooled to 0° C., diluted with 150 ml of water andmade basic with 50% sodium hydroxide solution. The precipitate iscollected by suction filtration, washed with water and dried to givecolorless crystals. Recrystallization from 40 ml of n-hexane gives 78.4%of product, mp 131.5°-132.5° C.

Analysis: Calculated for C₂₁ H₂₅ NO: 82.04%C; 8.20%H; 4.56%N. Found:82.30%C; 8.21%H; 4.58%N.

EXAMPLE 2cis-4-dimethylaminospiro[cyclohexane-1,1'-(3'H)-isobenzofuran]-3'-onehydrochloride

A solution of 4.50 g ofcis-4-dimethylamino-1-[2-(4,5-dihydro-4,4-dimethyl-2-oxazlyl)phenyl]cyclohexanolin 85 ml of 3 N hydrochloric acid is refluxed for 5 hours and thenevaporated in vacuo to an oil. The oil is dissolved in 50 ml ofdichloromethane, washed with 30 ml of 5% sodium hydroxide solution andwith water, dried over anhydrous sodium sulfate and concentrated. Theoily residue is dissolved in 20 ml of ethanol. The solution is madeacidic with hydrogen chloride/ether and treated with 50 ml of ether. Theprecipitate is collected by suction filtration and recrystallized fromethanol/ether (50 ml/50 ml) to yield 77.6% of product as colorlesscrystals, mp 275°-276° C.

Analysis: Calculated for C₁₅ H₁₉ NO₂.HCl: 63.94%C; 7.15%H; 12.58%Cl;4.97%N. Found: 64.07%C; 7.13%H; 12.31%Cl; 4.86%N.

EXAMPLE 3cis-4-Dimethylamino-3'-hydroxy-3'-phenylspiro[cyclohexane-1,1'(3'H)-isobenzofuran]

A solution of 8.45 g ofcis-4-dimethylaminospiro[cyclohexane-1,1'(3'H)-isobenzofuran]-3-onehydrochloride in 150 ml of dichloromethane is stirred with a solution of1.28 g of sodium hydroxide in 50 ml of water for 1/2 hour. The organicphase is separated, washed with water, dried over anhydrous sodiumsulfate and concentrated to an oil. The oil is dissolved in 100 ml ofdry tetrahydrofuran and added dropwise to 30 ml of cold (-30° C.)stirred 2.1 M phenyllithium in 70:30 benzene-ether. The solution isstirred at 0° C. for 1 hour, diluted wither water and extracted withether. The organic phase is washed with water, dried over anhydroussodium sulfate and evaporated to an oil. The oil is diluted with 100 mlof cyclohexane and suction filtered. The filtrate is cooled overnightand the precipitate is collected by suction filtration. The precipitateis recrystallized from 40 ml of methanol. The filter cake andrecrystallized material are combined and recrystallized fromtoluene/hexane (40 ml/50 ml) to provide 32.2% of product, mp 184°-185.5°C.

Analysis: Calculated for C₂₁ H₂₅ NO₂ : 77.98%C; 7.79%H; 4.33%N. Found:78.05%C; 7.85%H; 4.22%N.

EXAMPLE 4cis-4-Dimethylaminospiro[cyclohexane-1,1'-(3'H)-isobenzofuran]hydrochloride

A solution of 5.63 g of4-dimethylaminospiro[cyclohexane-1,1'-(3'H)-isobenzofuran]-3-onehydrochloride in 100 ml of dichloromethane is stirred with a solution of0.88 g of sodium hydroxide in 40 ml of water. The organic phase isseparated, washed with water, dried over anhydrous sodium sulfate andconcentrated. The oil is dissolved in 50 ml of dry tetrahydrofuran withstirring. After the addition is complete, the mixture is kept at roomtemperature for 30 minutes and then refluxed overnight. The solution iscooled to 0° C. and 19 ml of 6 N hydrochloric acid is added dropwise.The mixture is then refluxed for 5 hours and the solvents are evaporatedin vacuo to give an oil which is distributed between ether and water.The pH of the aqueous layer is adjusted to 10 with 50% sodium hydroxidesolution. The layers are separated and the aqueous layer is extractedwith ether. The combined extracts are washed with water, dried overanhydrous sodium sulfate and evaporated to an oil. The oil is dissolvedin 40 ml of ethanol and made acidic with a slight excess of hydrogenchloride/ether. After the addition of 60 ml of ether, the precipitate iscollected. The precipitate is recrystallized from ethanol/ether (25ml/35 ml) to give 64.9% of product, mp 248°-249° C.

Analysis: Calculated for C₁₅ H₂₁ NO.HCl: 67.28%C; 8.28%H; 13.24%Cl;5.23%N. Found: 67.45%C; 8.38%H; 13.15%Cl; 5.03%N.

EXAMPLE 5cis-dimethylamino-3'-hydroxy-3'-methylspiro[cyclohexane-1,1'(3'H)-isobenzofuran]

A solution of 5.63 g ofcis-4-dimethylaminospiro[cyclohexane-1,1'-(3'H)-isobenzofuran]-3-onehydrochloride in 150 ml of dichloromethane is stirred for 30 minuteswith a solution of 0.90 g of sodium hydroxide in 40 ml of water. Theorganic phase is washed with water, dried over anhydrous sodium sulfateand concentrated to an oil. The oil is dissolved in 50 ml of dry etherand added dropwise to 11 ml of 2.74 M methylmagnesium chloride intetrahydrofuran and 10 ml of tetrahydrofuran. The mixture if refluxedfor 4 hours, cooled and diluted with 30 ml of water. The organic phaseis decanted and the residue is extracted with ether (3×50 ml). Thecombined organic phase is washed with water (2×50 ml), dried overanhydrous sodium sulfate and concentrated to an oil. The oil isdissolved in 10 ml of ether and 40 ml of hexane is added. After cooling(10 minutes at 5°-10° C.), the precipitate is collected.Recrystallization from toluene/hexane (20 ml/30 ml) provides 59.7% ofproduct, mp 140.5°-141.5° C.

Analysis: Calculated for C₁₆ H₂₃ NO: 73.53%C; 8.87%H; 5.36%N. Found:73.87%C; 9.10%H; 5.17%N.

EXAMPLE 6cis-4-Dimethylamino-3'-hydroxy-3'-(4-methylphenyl)spiro[cyclohexane-1,1'(3'H)-isobenzofuran]

A solution of 5.63 g ofcis-4-dimethylaminospiro[cyclohexane-1,1'-(3'H)-isobenzofuran]-3-onehydrochloride in 150 ml of dichloromethane is stirred for 30 minuteswith a solution of 0.90 g of sodium hydroxide in 40 ml of water, driedover anhydrous sodium sulfate and concentrated to an oil. The oil isdissolved in 50 ml of dry tetrahydrofuran and added dropwise to 15 ml of1.96 M 4-methylphenylmagnesium bromide in ether. The mixture is refluxeffor 4 hours, coold and diluted with 30 ml of water. The organic phase isdecanted and the residue is extracted with ether (3×50 ml). The combinedorganic phase is washed with water (2×50 ml), dried over anhydroussodium sulfate and concentrated to an oil. The oil is crystallized fromtoluene/hexane (125 ml/75 ml) to provide 60.7% of product, mp 196°-197°C.

Analysis: Calculated for C₂₂ H₂₇ NO₂ : 78.30%C; 8.06%H; 4.15%N. Found:78.57%C; 8.08%H; 3.93%N.

EXAMPLE 7cis-4-Dimethylamino-3'-ethyl-3'-phenylspiro[cyclohexane-1,1'(3'H)-isobenzofuran]hydrochloride

To a cold (-50° C.) solution of 4.61 g ofcis-4-dimethylamino-3'-phenylspiro[cyclohexane-1,1'(3'H)-isobenzofuran]in 60 ml of dry tetrahydrofuran is added dropwise 15 ml of 2.2 Mn-butyllithium in n-hexane. After 30 minutes at -50° C., a solution of1.60 g (0.0147 M) ethyl bromide in 10 ml of dry tetrahydrofuran is addeddropwise. After 1.5 hours at -50° C. and 3 hours at room temperature,100 ml of water and 200 ml of ether are added. The organic layer isseparated, washed with water (2×50 ml), dried over anhydrous sodiumsulfate and concentrated to an oil. The oil is dissolved in 30 ml ofethanol and made acidic with a slight excess of hydrogen chloride/ether.After addition of 70 ml of ether and cooling overnight (5° C.), theproduct is collected by filtration, washed with ether and dried toprovide 83.3% of product, mp 266°-267° C.

Analysis: Calculated for C₂₃ H₂₉ NO.HCl: 74.27%C; 8.13%H; 9.53%Cl;3.77%N. Found: 74.31%C; 8.20%H; 9.39%Cl; 3.57%N.

EXAMPLE 8cis-4-Dimethylamino-3'-phenyl-3'-(n-propyl)spiro[cyclohexane-1,1'(3'H)-isobenzofuran]hydrochloride

To a cold (-50° C.) solution of 3.07 g ofcis-dimethylamino-3'-phenylspiro[cyclohexane-1,1'(3'H)-isobenzofuran] in40 ml of dry tetrahydrofuran is added dropwise 11 ml of 2.1 Mn-butyllithium (hexane). After 30 minutes at -50° C., a solution of 1.70g of n-propyl iodide in 7 ml of dry tetrahydrofuran is added dropwise at-50° C. After 40 minutes at -50° C. and 2 hours at room temperature, 100ml of water and 200 ml of ether are added. The organic phase isseparated, washed with water (3×50 ml), dried over anhydrous sodiumsulfate, filtered and concentrated to an oil. The oil is dissolved in 20ml of ether and made acidic with a slight excess of hydrogenchloride/ether. To this mixture is added 50 ml of ether and theprecipitate is isolated by filtration. Recrystallization fromethanol-ether (15 ml-25 ml) provides 57.0% of product, mp 218°-219.5° C.

Analysis: Calculated for C₂₄ H₃₁ NO.HCl; 74.68%C; 8.36%H; 3.63%N;9.18%Cl. Found: 74.42%C; 8.41L %H; 3.26%N; 9.08%Cl.

EXAMPLE 9cis-4-Dimethylamino-3'-(4-methylphenyl)spiro[cyclohexane-1,1'-(3'H)-isobenzofuran]hydrochloride

A solution of 2.95 g of2-[4-(dimethylamino)-1-hydroxyclohexyl]-α-(4-methylphenyl)benzenemethanolin 17 ml of acetic acid and 3 ml of concentrated hydrochloric acid isheated to reflux for 10 minutes. After the solvents are removed underreduced pressure, the residue is dissolved in 100 ml of dichloromethaneand concentrated to an oil. The oil is dissolved in 25 ml of ether andthe solution is filtered and made acidic with a slight excess ofhydrogen chloride/ether. The precipitate is collected by filtration andrecrystallized from methanol-ether (5 ml-20 ml) to provide 80.4% ofproduct, mp 243°-244° C.

Analysis: Calculated for C₂₂ H₂₇ NO.HCl: 73.82%C; 7.88%H; 3.91%N;9.90%Cl. Found: 73.53%C; 7.59%H; 3.68%N; 9.79%Cl.

EXAMPLE 10cis-4-Dimethylamino-3'-methyl-3'-phenylspiro[cyclohexane-1,1'(3'H)-isobenzofuran]oxalate

To a cold (-50° C.) solution of 4.61 g ofcis-4-dimethylamino-3'-phenylspiro[cyclohexane-1,1'(3'H)-isobenzofuran]in 50 ml of dry tetrahydrofuran is added dropwise 17 ml of 2.1 Mn-butyllithium (hexane). After 30 minutes at -50° C., a solution of 1.87g of dimethyl sulfate in 8 ml of dry tetrahydrofuran is added dropwiseat -50° C. After 45 minutes at -50° C. and 2.5 hours at roomtemperature, 100 ml of water and 200 of ether are added. The organicphase is separated, washed with water (3×50 ml), dried over anhydroussodium sulfate, filtered and treated with a solution of 1.8 g of oxalicacid in 12 ml of ethanol. After cooling (1 hour at 10° C.), theprecipitate is collected by filtration, washed with ether and dried.Recrystallization from ethanol/ether (celite) and methanol/etherprovides 68.0% of product, mp 176°-178° C.

Analysis: Calculated for C₂₂ H₂₇ NO.C₂ H₂ O₄ : 70.05%C; 7.10%H; 3.40%N.Found: 69.38%C; 7.14%H; 3.21%N.

EXAMPLE 11cis-4-Dimethylamino-3'-methylspiro[cyclohexane-1,1'(3'H)-isobenzofuran]hydrochloride

A solution of 1.94 g of2-[cis-(4-dimethylamino-1-hydroxycyclohexyl)]α-methylbenzenemethanol in30 ml of acetic acid and 4 ml of concentrated hydrochloric acid isheated to reflux for 15 minutes. The solvents are removed under reducedpressure and the oily residue dissolved in 100 ml of dichloromethane.The solution is washed with 5% sodium hydroxide solution, dried overanhydrous sodium sulfate and concentrated to an oil. The oil isdissolved in 20 ml of ether. The solution is made acidic with a slightexcess of hydrogen chloride/ether (8/40 ml) to provide 94.7% of product,mp 210°-212° C.

Analysis: Calculated for C₁₆ H₂₃ NO.HCl: 68.19%C; 8.58%H; 12.58%Cl;4.97%N. Found: 68.38%C; 8.50%H; 12.62%Cl; 5.01%N.

EXAMPLE 12cis-4-{N-[3-(4-Fluorobenzoyl)-prop-1-yl]-N-methyl}amino-3'-phenylspiro[cyclohexane-1,1'(3'H)-isobenzofuran]hydrobromide

A solution of 2.47 g ofcis-4-methylamino-3'-phenylspiro[cyclohexane-1,1'(3'H)-isobenzofuran]hydrochloridein 25 ml of methanol and 10 ml of water is made basic with 10% sodiumhydroxide solution. The solution is diluted with 50 ml of water andafter cooling the product is filtered, washed with water and dried togive the starting material (free base), mp 115°-116° C.

A solution of 1.95 g of free base in 35 ml of dimethylformamide isstirred with 1.11 g of potassium iodide, 1.85 g of potassium carbonateand 1.72 g of 4-chloro-p-fluoro-butyrophenone ethylene ketal at 90° C.for 24 hours. The solvent is removed under reduced pressure (0.1 mm) andthe residue dissolved in 100 ml of ethanol. The solution is filtered,washed with water, dried over anhydrous sodium sulfate and concentratedto an oil. The oil is dissolved in 10 L ml of ethanol and stirred with aslight excess of hydrogen bromide/ether for 1 hour at room temperature.The mixture is diluted with 50 ml of ethanol and the precipitation iscollected by suction filtration. Recrystallization from methanol-ether(40/40 ml) provides 61.5% of product, mp 241°-243° C.

Analysis: Calculated for C₃₀ H₃₂ FNO₂.HBr: 66.91%C; 6.18%H; 3.53%F;2.60%N. Found: 66.74%C; 6.25%H; 3.48%F; 2.72%N.

EXAMPLE 134-Amino-3'-phenylspiro[cyclohexane-1,1'(3'H)-isobenzofuran]hydrochloride

A solution of 6.07 g of4-oximino-3'-phenylspiro[cyclohexane-1,1'(3'H)-isobenzofuran] in 80 mlof dry tetrahydrofuran is added to a suspension of 2.00 g of lithiumaluminum hydride in 60 ml of dry tetrahydrofuran and the mixture isrefluxed for 80 minutes. After cooling and hydrolyzing with 25 ml ofwater the mixture is extracted with 100 ml of ethanol and 50 ml ofdichloromethane. The combined organic phase is washed with water, driedover anhydrous potassium carbonate and evaporated to an oil. The oil isdissolved in 100 ml of methanol and the solution is filtered. Thefiltrate is concentrated in vacuo to a volume of 30 ml and made acidicusing hydrogen chloride/ether and 70 ml of ethanol. The precipitate iscollected, washed with water and dried. Recrystallization frommethanol/ether (40 ml/60 ml) gives 51.6% of product, mp>260° C.

Analysis: Calculated for C₁₉ H₂₁ NO.HCl.1/4H₂ O: 71.24%C; 7.08%H;11.07%Cl; 4.37%N. Found: 71.45%C; 6.92%H; 11.02%Cl; 4.45%N.

EXAMPLE 144-Amino-3'-cyclohexylspiro[cyclohexane-1,1'(3'H)-isobenzofuran]hydrochloride

A mixture of 1.50 g of4-methoximino-3'-phenylspiro[cyclohexane-1,1'(3'H)-isobenzofuran]hydrochloride,150 ml of acetic acid and 0.5 g of platinum oxide is hydrogenated at 50psi and room temperature for 41/2 hours. After filtration and removingthe solvent, the oily product is dissolved in 100 ml of dichloromethaneand washed with 5% sodium hydroxide solution and water. After dryingover anhydrous sodium sulfate, the solvent is removed in vacuo to givean oil. The oil is dissolved in 10 ml of methanol and the solution ismade acidic using hydrogen chloride/ether. After addition of 50 ml ofether, the precipitate is suction filtered, washed with ether and driedto give 66.0% of product, mp ˜220°-224° C.

Analysis: Calculated for C₁₉ H₂₇ NO.HCl.1/4H₂ O: 69.92%C; 8.80%H;10.86%Cl; 4.29%N. Found: 69.80%C; 8.56%H; 11.01%Cl; 4.37%N.

EXAMPLE 15cis-4-Dimethylamino-3'-hydroxy-3'-(2-methylphenyl)spiro[cyclohexane-1,1'(3'H)-isobenzofuran]

A 100 ml 3-neck flask equipped with a mechanical stirrer, droppingfunnel bearing a nitrogen inlet tube and reflux condenser is chargedwith 0.804 g of magnesium turnings and 5 ml of anhydroustetrahydrofuran. The dropping funnel is charged with a solution of 5.13g of 2-bromotoluene and sufficient anhydrous tetrahydrofuran to give atotal volume of 15 ml. A portion (6 ml) of the 2-bromotoluene solutionand crystal of iodine are added to the magnesium. The stirred mixture isheated to reflux under nitrogen and refluxed until the reactioninitiates. At this point, heating is discontinued and the reaminingsolution of 2-bromotoluene is added at such a rate as to maintainrefluxing. The mixture is refluxed until most of the magnesiumdissolves. The dark colored solution is cooled (water bath) and asolution of 6.0 g ofcis-4-dimethylaminospiro[cyclohexane-1,1'(3'H)-isobenzofuran]-3'-one and10 ml of anhydrous tetrahydrofuran is added dropwise over 20 minutes.The resultant suspension is stirred for 20 minutes at room temperature,diluted with 20 ml of tetrahydrofuran and refluxed for 45 minutes. Thecooled mixture is quenched by addition of a solution of 8.0 g ofammonium chloride in 35 ml of water. The mixture is suction filtered andthe filter cake is washed twice with dichloromethane. The combinedfiltrates are treated with excess 5% sodium hydroxide solution and 70 mlof dichloromethane. The phases are separated and the aqueous phase isextracted with a total of 500 ml of dichloromethane. The previouslyextracted filter cake appeared to contain organic material and is washedwith methanol. The methanol washings are added to the organic phase. Thecombined organic phase is dried over anhydrous sodium sulfate, filteredand evaporated to a crisp foam. The foam is crystallized from 40 ml ofisopropanol. A small amount of crystalline material separates on coolingto room temperature and the mother liquor is decanted. Cooling andscratching the mother liquor resulted in further crystallization. Themixture is stirred for 24 hours at room temperature and the precipitateis collected by suction filtration and dried in vacuo at 40° C. toafford 49.8% of product, mp 161°-163° C.

Analysis: Calculated for C₂₂ H₂₇ NO₂ : 78.30%C; 8.07%H; 4.15%N. Found:78.12%C; 8.22%H; 3.97%N.

EXAMPLE 16cis-4-Dimethylamino-3'-(2-methylphenyl)spiro[cyclohexane-1,1'(3'H)-isobenzofuran]

A solution of 3.7 g ofcis-4-dimethylamino-3'-hydroxy-3'-(2-methylphenyl)spiro[cyclohexane-1,1'(3'H)-isobenzofuran]and 40 ml of 97% formic acid solution is refluxed with stirring for 2hours. Excess formic acid is removed on a rotary evaporator at 60° C.and the residue is diluted with 50 ml of water. The solution is madestrongly alkaline with 50% sodium hydroxide solution and is extractedthrice with 50 ml portions of dichloromethane. The combined organicphase is dried over anhydrous sodium sulfate, filtered and evaporated togive a solid residue. The residue is dissolved in 35 ml of boilinghexane and the solution is filtered. The filtrate is concentrated toapproximately half volume by boiling off the excess hexane. Aftercooling to room temperature the crystalline precipitate is collected bysuction filtration and the filter cake is washed with a little hexaneand dried in vacuo at room temperature to afford 74.0% of product, mp118.5°-119.5° C.

Analysis: Calculated for C₂₂ H₂₇ NO: 82.20%C; 8.47%H; 4.36%N. Found:82.11%C; 8.64%H; 4.08%N.

EXAMPLE 17trans-4-Dimethylaminospiro[cyclohexane-1,1'(3'H)-isobenzofuran]-3'-onehydrochloride

A 12-l, three-neck flask is charged with 296 of benzanilide and purgedovernight with dry nitrogen. Anhydrous tetrahydrofuran (4000 ml) isadded and the stirred solution is chilled to -45° C. (benzanilide beginsto separate from solution). The stirred suspension is treated with atotal of 3.0 M of n-butyllithium in hexane (2.2 M solution). The rate ofaddition is controlled such that the temperature remains between -30°and -20° C. After addition is complete, the solution is stirred for 60minutes at 0° C. (ice water bath). During this time the solution becomesred in color. The solution is chilled to -35° to -40° C. and a solutionof 105.9 g of 4-dimethylaminocyclohexanone in a little anhydroustetrahydofuran is added dropwise over 30 minutes. The resultant redcolored turbid mixture is stirred 45 minutes at -40° to -45° C. and thenallowed to warm to -10° C. The mixture is stirred at 0° C. (ice waterbath) for 1 hour, followed by quenching with 300 ml of water.Dichloromethane (1000 ml) and dilute hydrochloric acid (1500 ml preparedby diluting 420 ml of concentrated hydrochloric acid with water) areadded with cooling (internal temperature reaches 32° C.), followed bystirring overnight at room temperature. The phases are separated and theupper dichloromethane phase is washed with a total of 3000 ml of water.The aqueous phases are combined and made strongly alkaline with 50%sodium hydroxide solution. The mixture is extracted with a total of 2500ml of dichloromethane and the combined extracts are dried over anhydroussodium sulfate, suction filtered and evaporated to an oil. The volatileamines (aniline, 4-dimethylaminocyclohexanone) are removed by vacuumdistillation at 100° C. The residual oil is dissolved in 200 ml ofdichloromethane and the solution is diluted with anhydrous ether (2000ml). A small amount of amorphorous precipitate is removed by filtration.The filtrate is treated with excess ethereal hydrochloric acid and theresultant suspension is stirred for 45 minutes to break up theaggregates. The crystalline precipitate is collected by suctionfiltration and the filter cake is washed twice with ether, and dried invacuo at 35° C. overnight over sodium hydroxide pellets.Recrystallization from 550 ml of methanol (the solution is allowed tostand overnight at room temperature) affords 14.0% of the trans-isomer,mp 275°-283° C.

Analysis: Calculated for C₁₅ H₁₉ NO₂.HCl: 63.93%C; 7.15%H. Found:63.87%C; 7.16%H.

Evaporation of the filtrate and recrystallization of the residue fromisopropanol provides 38.7% of the cis-isomer.

EXAMPLE 18trans-4-Dimethylamino-3'-hydroxy-3'-phenylspiro[cyclohexane-1,1'(3'H)-isobenzofuran]

A 250 ml three-neck flask equipped with a mechanical stirrer, refluxcondenser and 50 ml dropping funnel bearing a nitrogen inlet tube ischarged with 2.19 g of magnesium turnings and 14 ml of anhydroustetrahydrofuran. The system is flushed with dry nitrogen and thedropping funnel is charged with a solution of 14.13 g of bromobenzeneand 50 ml of anhydrous tetrahydofuran. A portion (10 ml) of thebromobenzene solution is added at once and the stirred mixture is heatedto reflux (steam bath). After initiation of the reaction, heating isdiscontinued and the remainder of the bromobenzene solution is added atsuch a rate as to maintain reflux. After addition is complete, themixture is heated under reflux until most of the magnesium hasdissolved. The phenylmagnesium bromide solution is chilled (10° C.) anda solution oftrans-4-dimethylaminospiro[cyclohexane-1,1'(3'H)-isobenzofuran]-3'-oneand 100 ml of anhydrous tetrahydrofuran is added dropwise over 45minutes with stirring and cooling.

After the addition is complete, the mixture is stirred 15 minutes atroom temperature, followed by refluxing for 40 minutes. To the cooledmixture is added a solution of 24.0 g of ammonium chloride and 80 ml ofwater with stirring. The mixture is suction filtered and the filter cakeis washed twice with dichloromethane. The combined filtrates are treatedwith excess 5% sodium hydroxide solution and additional dichloromethaneis added. The phases are separated and the aqueous phase is extractedtwice with dichloromethane. The combined organic phase is dried overanhydrous sodium sulfate, suction filtered and evaporated to an oilwhich foamed. Trituration with dichloromethane and evaporation affords asolid. The filter cake containing magnesium salts is suspended in 100 mlof 5% sodium hydroxide solution and stirred several minutes. The mixtureis suction filtered and the filter cake is washed twice with methanol.The combined filtrates are extracted with dichloromethane to provide anadditional amount of solid. Recrystallization of the combined solidsfrom 125 ml of toluene affords product, mp 179°-185° C. Furthertreatment of the filter cake with alkali (stirred three days at roomtemperature with 100 ml of 5% sodium hydroxide solution and 50 ml ofdichloromethane affords additional product, mp 184°-188° C. Total yield73.1%.

Analysis: Calculated for C₂₁ H₂₅ NO₂ : 77.98%C; 7.79%H; 4.33%N. Found:78.16%C; 7.39%H; 3.98%N.

EXAMPLE 19trans-4-Dimethylamino-3'-phenylspiro[cyclohexane-1,1'(3'H)-isobenzofuran]

A solution of 3.7 g oftrans-4-dimethylamino-3'-hydroxy-3'-phenylspiro[cyclohexane-1,1'(3'H)-isobenzofuran]and 42 ml of 97% formic acid solution is heated under reflux for 2.0hours. Excess formic acid is removed under reduced pressure and theresidue is dissolved in 200 ml of water. The solution is made alkalinewith 5% sodium hydroxide solution and extracted thrice with 100 mlportions of dichloromethane. The combined organic phase is dried overanhydrous sodium sulfate, suction filtered and evaporated under reducedpressure to a yellow colored solid. Recrystallization from 10 ml ofacetonitrile affords 66.2% of product, mp 83.5°-85° C.

Analysis: Calculated for C₂₁ H₂₅ NO: 82.04%C; 8.20%H; 4.56%N. Found:82.25%C; 8.41%H; 4.54%N.

EXAMPLE 20trans-4-methylphenoxycarbonylamino-3'-phenylspiro[cyclohexane-1,1'(3'H)-isobenzofuran]

A stirred solution of 4.61 g oftrans-4-dimethylamino-3'-phenylspiro[cyclohexane-1,1'(3'H)-isobenzofuran]and 20 ml of sieve dried dichloromethane is treated dropwise over onehour with a solution of 2.82 g of phenylchloroformate and 15 ml of sievedried dichloromethane. The resultant solution is stirred overnight atroom temperature during which a colorless precipitate separates.Evaporation under reduced pressure affords a gel which fails to solidifyon trituration with anhydrous ether. The mixture is evaporated and theresidue is dissolved in dichloromethane and washed with 15 ml each ofwater and 5% sodium hydroxide solution. The dried anhydrous sodiumsulfate organic phase is concentrated under reduced pressure to aslightly turbid, viscous oil. The oil is dissolved in 30 ml ofdichloromethane and the solution is treated with 1.0 g ofphenylchloroformate, followed by stirring for 96 hours at roomtemperature with exclusion of moisture. Work up as described in Example23, and trituration with ether affords a solid which is collected bysuction filtration. The solid is dissolved in 70 ml of dichloromethaneand the solution is washed with 5% sodium hydroxide solution. Theorganic phase is dried over anhydrous sodium sulfate, suction filteredand evaporated to an oil which solidifies on trituration with ether.Recrystallization of the solid from 18 ml of 95% ethanol affords 37.1%of product, mp 127°-134° C.

Analysis: Calculated for C₂₇ H₂₇ NO₃ : 78.42%C; 6.58%H; 3.39%N. Found:78.39%C; 6.58%H; 3.08%N.

EXAMPLE 21cis-4-Dimethylamino-3'-(4-fluorophenyl)-3'-hydroxyspiro[cyclohexane-1,1'(3'H)-isobenzofuran]hemihydrate

A 10 ml portion of a solution of 24 g of 4-bromofluorobenzene and 50 mlof anhydrous tetrahydrofuran is added to a mixture of 3.72 g ofmagnesium turnings and 20 ml of anhydrous tetrahydrofuran. The mixtureis heated (steam bath) with stirring until the reaction initiates andthe steam bath is removed. The remaining 4-bromofluorobenzene solutionis then added at such a rate as to maintain a gentle reflux. Afteraddition is complete, the mixture is heated under reflux until most ofthe magnesium dissolves. The dark colored solution is cooled (10° C.,bath temperature) and diluted with 50 ml of anhydrous tetrahydrofuran.To the cooled, stirred solution is added dropwise over 15 minutes, afiltered solution ofcis-4-dimethylaminospiro[cyclohexane-1,1'(3'H)-isobenzofuran]-3'-one(29.0 g) and 70 ml of anhydrous tetrahydrofuran. The resultant darkcolored solution is stirred for 15 minutes at 15° C., and 60 minutes atroom temperature, during which time a precipitate separates. The mixtureis heated under reflux for 50 minutes, cooled and allowed to standovernight at room temperature. The mixture is decanted into 250 ml ofwater, made alkaline with 5% sodium hydroxide solution and suctionfiltered. The filter cake is extracted with four 100 ml portions ofdichloromethane using each extract to wash the aqueous phase. Thecombined dried anhydrous sodium sulfate organic phase is evaporated toafford a crude product. Recrystallization from 50 ml of 95% ethanolaffords an impure product and additional impure product is obtained fromthe mother liquor. The filter cake of magnesium salts is treated withthree 200 ml portions of dichloromethane and a little methanol. Thecombined, dried anhydrous sodium sulfate organic phase affords a crudematerial, which after recrystallization from 200 ml of 95% ethanolprovides a reasonably pure product, mp 140°-158° C. The mother liquorprovides additional material. Recrystallization from 100 ml of 95%ethanol affords additional product, mp 140°-159° C. The total yield ofpurified material is 54.2%.

Analysis: Calculated for C₂₁ H₂₄ FNO₂.O.5H₂ O: 71.98%C; 7.19%H; 4.00%N;5.42%F. Found: 71.52%C; 7.27%H; 3.87%N; 5.28%F.

A dried (Abderhalden pistol, toluene) sample has

Analysis: Calculated for C₂₁ H₂₄ FNO₂ : 73.87%C; 7.08%H; 4.10%N. Found:73.33%C; 7.11%H; 3.86%N.

EXAMPLE 22cis-4-Dimethylamino-3'-(4-fluorophenyl)spiro[cyclohexane-1',1'(3'H)-isobenzofuran]

A solution of 5.12 g ofcis-4-dimethylamino-3'-(4-fluorophenyl)-3'-hydroxyspiro[cyclohexane-1,1'(3'H)-isobenzofuran]and 50 ml of 97% formic acid is heated 2 hours under reflux withstirring. Excess formic acid is removed under reduced pressure and theresidue is dissolved in 200 ml of water. The solution is made alkalinewith 5% sodium hydroxide solution and extracted thrice with 100 mlportions of dichloromethane. The organic phase is dried over anhydroussodium sulfate, suction filtered and evaporated to afford a yellowcolored solid. Recrystallization from 15 ml of acetonitrile affords agreen colored solid. Recrystallization of this solid from 15 ml ofacetonitrile with decolorization (Darco G60 activated carbon) provides30% of product, mp 104.5°-106° C.

Analysis: Calculated for C₂₁ H₂₄ FNO: 77.51%C; 7.43%H; 4.30%N; 5.84%F.Found: 77.60%C; 7.47%H; 4.07%N; 5.92%F.

EXAMPLE 23cis-4-Methylphenoxycarbonylamino-3'-(2-methylphenyl)spiro[cyclohexane-1,1'(3'H)-isobenzofuran]

A stirred, cooled (bath temperature 15° C.) solution of 6.42 g ofcis-4-dimethylamino-3'-(2-methylphenyl)spiro[cyclohexane-1,1'(3'H)-isobenzofuran]and 20 ml of sieve dried dichloromethane is treated with exclusion ofmoisture over 40 minutes with a solution of 3.45 g of redistilledphenylchloroformate and 20 ml of dichloromethane. The resultant solutionis stirred for 24 hours at room temperature and is then allowed to standfor 24 hours at room temperature with exclusion of moisture. Thesolution is washed thoroughly with 30 ml each of 5% sodium hydroxidesolution and water, dried over anhydrous sodium sulfate and evaporatedto an oil which forms a crisp, dry foam. Crystallization from 150 ml ofhexane with filtration provides 65.5% of product, mp 122°-125.5° C.

Analysis: Calculated for C₂₈ H₂₉ NO₃ : 78.66%C; 6.84%H; 3.28%N. Found:

EXAMPLE 24trans-4-Methylamino-3'-phenylspiro[cyclohexane-1,1'(3'H)-isobenzofuran]hydrochloride

A stirred suspension of 5.82 g oftrans-4-methylphenoxycarbonylamino-3'-phenylspiro[cyclohexane-1,1'(3'H)-isobenzofuran]and alcoholic potassium hydroxide [prepared from 8.25 g of potassiumhydroxide pellets, 2.5 ml of water and 58 ml of n-propanol] is heatedovernight under reflux. Excess n-propanol is removed from the cooledsolution on a rotary evaporator and the residual syrup is diluted withwater and extracted twice with 125 ml portions of dichloromethane. Thecombined, dried over anhydrous sodium sulfate organic phase is filteredand concentrated to an oil. A solution of the oil and 50 ml of anhydrousether is filtered and treated with a slight excess of ethereal hydrogenchloride. The precipitate is collected by suction filtration and driedin vacuo at room temperature over sodium hydroxide pellets.Recrystallization of the crude product from 160 ml of 95% ethanolaffords 44.9% of product, mp 286°-290° C. (dec).

Analysis: Calculated for C₂₀ H₂₃ NO.HCl: 72.82%C; 7.33%H; 4.25%N;10.75%Cl. Found: 72.78%C; 7.67%H; 4.25%N; 10.69%Cl.

EXAMPLE 25cis-4-Methylamino-3'-(2-methylphenyl)spiro[cyclohexane-1,1'(3'H)-isobenzofuran]

A stirred suspension of 12 g ofcis-4-methylphenoxycarbonylamino-3'-(2-methylphenyl)spiro[cyclohexane-1,1'(3'H)-isobenzofuran]and alcoholic potassium hydroxide [prepared from 16.5 g of potassiumhydroxide pellets, 5 ml of water and 80 ml of n-propanol] is heatedovernight under reflux. Excess n-propanol is removed from the cooledsolution on a rotary evaporator. The residue is diluted with water andextracted thrice with 150 ml portions of dichloromethane. The driedanhydrous sodium sulfate organic phase is evaporated to an oil. Work upas described in Example 24 affords 10.3 g of crude oil, which isdissolved in 50 ml of anhydrous ether and treated with excess etherealhydrochloric acid. The precipitate is collected by suction filtration,washed once with anhydrous ether and dried in vacuo at room temperatureover sodium hydroxide pellets. Recrystallization of the crude productfrom 700 ml of isopropanol affords 53.5% of product, mp 275°-277.5° C.

Analysis: Calculated for C₂₁ H₂₅ NO.HCl: 73.56%C; 7.35%H; 4.09%N;10.34%Cl. Found: 73.22%C; 7.73%H; 3.83%N; 10.04%Cl.

EXAMPLE 26cis-3'-(4-Fluorophenyl)-4-methylphenoxycarbonylaminospiro[cyclohexane-1,1'(3'H)-isobenzofuran]

A stirred solution of 3.07 g ofcis-4-dimethylamino-3'-(4-fluorophenyl)spiro[cyclohexane-1,1'(3'H)-isobenzofuran]and 7 ml of sieve dried dichloromethane is treated over 2 minutes with asolution of 1.62 g of redistilled phenylchloroformate and 7 ml ofdichloromethane with water bath cooling. The resultant solution isstirred overnight at room temperature with exclusion of moisture and isthen allowed to stand five days at room temperature. The solution isdiluted with 70 ml of dichloromethane and washed thoroughly with 5%sodium hydroxide solution. The organic phase is dried over anhydroussodium sulfate and evaporated to an amorphorous solid. Recrystallizationfrom 50 ml of 95% ethanol affords 73.3% of product, mp 133°-137° C.

Analysis: Calculated for C₂₇ H₂₆ FNO₃ : 75.15%C; 6.07%H; 3.25%N. Found:74.87%C; 6.23%H; 3.09%N.

EXAMPLE 27cis-3'-(4-Chlorophenyl)-4-dimethylamino-3'-hydroxyspiro[cyclohexane-1,1'(3'H)-isobenzofuran]

To 0.87 g of magnesium turnings and 7 ml of anhydrous tetrahydrofuran isadded 5 ml of a solution of p-bromochlorobenzene (6.89 g) and 15 ml ofanhydrous tetrahydoruan (nitrogen atmosphere). The stirred mixture isheated (steam bath) to reflux to initiate formation of the Grignardreagent. The steam bath is removed and the remaining solution ofp-bromochlorobenzene is added at such a rate as to maintain a gentlyreflux. The resultant solution is heated under reflux until most of themagnesium dissolves, followed by cooling with a water bath. A solutionof 7.36 g ofcis-4-dimethylaminospiro[cyclohexane-1,1'(3'H)-isobenzofuran]-3'-one and10 ml of anhydrous tetrahydrofuran is added dropwise over 15 minutes,followed by stirring for 15 minutes. The brown solution is heated underfeflux for 30 minutes during which a brown precipitate separates. Themixture is then stirred for 3 hours at room temperature and allowed tostand overnight at room temperature. The mixture is poured into water(100 ml) and made alkaline with 5% sodium hydroxide solution. Themixture is suction filtered and the filter cake is washed well withdichloromethane and methanol. The filtrates are combined and dilutedwith methanol to a total volume of 500 ml. The resultant precipitate isremoved by suction filtration and the filtrate is concentrated to removethe organic solvents. The residual suspension is extracted thrice with200 ml portions of dichloromethane and the combined extracts dried overanhydrous sodium sulfate for 2 days. The mixture is suction filtered andthe filter cake is extracted with methanol to remove what appeared to bea crystalline precipitate. The filtrates are combined and evaporated toan amorphorous solid. The solid is dissolved in 30 ml of isopropanol andfiltered to remove an insoluble material. The filtrate is evaporated toan amorphorous solid. A solution of the solid in diethyl ether isfiltered and the filtrate evaporated to an amorphorous solid. Tworecrystallizations from acetonitrile and drying in an Abderhalden pistol(95% ethanol) affords 9.3% of product, mp 164°-168° C.

Analysis: Calculated for C₂₁ H₂₄ ClNO₂ : 70.48%C; 6.76%H; 3.91%N;9.91%Cl. Found: 70.30%C; 6.84%H; 4.00%N; 9.70%Cl.

EXAMPLE 28cis-3'-(4-Chlorophenyl)-4-dimethylaminospiro[cyclohexane-1,1'(3'H)-isobenzofuran]

A stirred solution of 6.92 g ofcis-3'-(4-chlorophenyl)-4-dimethylamino-3'-hydroxyspiro[cyclohexane-1,1'(3'H)-isobenzofuran]and 35 ml of 97% formic acid is heated under reflux for 2.5 hours.Excess formic acid is removed on a rotary evaporator, the residual syrupdiluted with 150 ml of water and the solution made alkaline with 10%sodium hydroxide solution. The mixture is extracted thrice with 150 mlportions of dichloromethane and the combined extracts are dried overanhydrous sodium sulfate. After filtration and concentration of thefiltrate, the residual oil is dissolved in 150 ml of anhydrous ether,the solution filtered and acidified with ethereal hydrogen chloride. Theprecipitate is collected, washed twice with anhydrous ether and dried at40° C. to afford crude material. Repeated recrystallization fromisopropanol affords 20.9% of product, mp 251°-253° C.

Analysis: Calculated for C₂₁ H₂₄ ClNO.HCl.H₂ O: 63.63%C; 6.87%H; 3.53%N.Found: 63.48%C; 6.51%H; 3.36%N.

EXAMPLE 28 Acis-3'-(4-Chlorophenyl)-4-dimethylaminospiro[cyclohexane-1,1'(3'H)-isobenzofuran]

A stirred solution of 8.42 g ofcis-3'-(4-chlorophenyl)-4-dimethylamino-3'-hydroxyspiro[cyclohexane-1,1'(3'H)-isobenzofuran]and 40 ml of 97% formic acid solution is heated 2 hours under reflux.Excess formic acid is removed on a rotary evaporator and the residualoil is diluted with 75 ml of water. The solution is made alkaline withexcess 10% sodium hydroxide solution, followed by extraction with three60 ml portions of dichloromethane. The combined organic phase is driedover anhydrous sodium sulfate, vacuum filtered and concentrated to anoil which is subjected to azeotropic distillation with 50 ml of toluene.The precipitate is isolated by vacuum filtration and washed with hexane.Drying in vacuo at 35° C. affords 91.5% of product, mp 110°-113° C.

Analysis: Calculated for C₂₁ H₂₄ ClNO: 73.78%C; 7.08%H. Found: 73.71%C;7.02%H.

EXAMPLE 29cis-3'-(4-Fluorophenyl)-4-methylaminospiro[cyclohexane-1,1'(3'H)-isobenzofuran]

A stirred suspension of 4.54 g ofcis-3'-(4-fluorophenyl)-4-methylphenoxycarbonylaminospiro[cyclohexane-1,1'(3'H)-isobenzofuran],6.0 g of potassium hydroxide pellets. 2.5 ml of water and 40 ml ofn-propanol is heated under reflux overnight. Dilution with water,removal of n-propanol on a rotary evaporator and extraction with two 100ml portions of dichloromethane affords a crude oil after evaporation. Asolution of the oil and 50 ml of anhydrous ether is treated with excessethereal hydrogen chloride. The precipitate is collected, washed twicewith anhydrous ether and dried in vacuo at 40° C. over sodium hydroxidepellets. Recrystallization of the crude material from 50 ml ofisopropanol and drying in an Abderhalden piston (toluene) affords 54% ofproduct, mp 263°-267° C.

Analysis: Calculated for C₂₀ H₂₂ FNO.HCl.0.5H₂ O: 67.69% C; 6.25% H;3.95% N. Found: 67.96% C; 6.64% H; 3.99% N.

EXAMPLE 30trans-4-{N-{3-[2-(4-Fluorophenyl)-1,3-dioxalon-2-yl]propyl}N-methyl}amino-3'-phenylspiro[cyclohexane-1,1'(3'H)-isobenzofuran]

A stirred mixture of 2.70 g oftrans-4-methylamino-3'-phenylspiro[cyclohexane-1,1'(3'H)-isobenzofuran],1.82 g of powdered potassum iodide, 1.82 g of anhydrous sodiumbicarbonate, 2.81 g of2-(3-chloropropyl)-2-(4-fluorophenyl)-1,3-dioxolan and 55 ml of sievedried dimethylformamide is heated at 90° C. overnight with exclusion ofmoisture. The cooled mixture is diluted with 80 ml of dichloromethane,vacuum filtered and the filtrate is concentrated to an oil. A solutionof the oil and 100 ml of dichloromethane is washed once with 70 ml of0.3 N sodium hydroxide solution and twice with 50 ml portions of water.The organic phase is dried over anhydrous sodium sulfate, filtered andevaporated to an oil which crystallizes on standing. Trituration withhexane affords a crystalline material which is vacuum filtered.Recrystallization from 15 ml of 95% ethanol affords 43% of product, mp92°-94° C.

Analysis: Calculated for C₃₂ H₃₆ FNO₃ : 76.61% C; 7.25% H. Found: 76.50%C; 7.21% H.

EXAMPLE 31cis-3'(4-Chlorophenyl)-4-methylphenoxycarbonylaminospiro[cyclohexane-1,1(3'H)-isobenzofuran]

A mixture of 1.60 g ofcis-3'-(4-chlorophenyl)-4-dimethylaminospiro[cyclohexane-1,1'(3'H)-isobenzofuran]hydrochloridemonohydrate, 100 ml of dichloromethane and 50 ml of 10% sodium hydroxidesolution is thoroughly agitated, the phases separated and the organicphase dried over anhydrous sodium sulfate. Concentration of the organicphase affords an oil which is dissolved in 10 ml of dichloromethane andtreated with 1.16 g of anhydrous anhydrous potassium carbonate and asolution of 1.32 g of redistilled phenylchloroformate and 10 ml ofdichloromethane. The stirred suspension is heated under reflux overnightwith exclusion of moisture. The cooled mixture is vacuum filtered. Thefiltrate is diluted with 70 ml of dichloromethane, washed thoroughlywith excess 10% sodium hydroxide solution, dried over anhydrous sodiumsulfate, vacuum filtered and concentrated to an oil. Tworecrystallizations from 95% ethanol affords 53% of product, mp 127°-133°C.

Analysis: Calculated for C₂₇ H₂₆ ClNO₃ : 72.39% C; 5.88% H. Found:72.20% C; 5.86% H.

EXAMPLE 32trans-4-[(3-p-Fluorobenzyl-prop-1-yl)methylamino]-3'-phenylspiro[cyclohexane-1,1'(3'H)-isobenzofuran]oxalate

A stirred solution of 4.46 g oftrans-4-{N-{3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl}-N-methyl}amino-3'-phenylspiro[cyclohexane-1,1'(3'H)-isobenzofuran],70 ml of methanol and 40 ml of 3 N hydrochloric acid is heated 2 hoursunder reflux, followed by standing at ambient temperature overnight. Acrystalline precipitate separates on standing and is collected by vacuumfiltration. The filter cake is washed twice with ether and dried at 40°C. over sodium hydroxide pellets in vacuo. A solution of 3.3 g of thecrude product and 70 ml of dichloromethane is washed with excess 10%sodium hydroxide solution, dried over anhydrous sodium sulfate andevaporated to an oil. A solution of this oil and 15 ml of methanol istreated with a solution of 0.675 g of oxalic acid and 10 ml of methanol.The resultant solution is concentrated to afford a tacky foam which istriturated with ether. The resultant precipitate is collected by vacuumfiltration and dried at ambient temperature in vacuo. Recrystallizationof the crude material from 15 ml of 95% ethanol affords 41.7% ofproduct, mp 161°-163° C.

Analysis: Calculated for C₃₀ H₃₂ FNO₂.C₂ H₂ O₄ : 70.17% C; 6.27% H.Found: 70.24% C; 6.23% H.

EXAMPLE 33cis-4-{N-[3-(4-Fluorobenzoyl)prop-1-yl]-N-methyl}amino-3'-(2-methylphenyl)spiro[cyclohexane-1,1'(3'H)-isobenzofuran]hydrochloride

A solution of 4.50 g ofcis-4-methylamino-3'-(2-methylphenyl)spiro[cyclohexane-1,1'(3'H)-isobenzofuran]hydrochlorideand 70 ml of dichloromethane is washed with excess 10% sodium hydroxidesolution. The organic phase is dried over anhydrous sodium sulfate,filtered and evaporated to afford an oil which crystallizes. A stirredsuspension of the crystalline free base, 2.61 g of finely powderedpotassium iodide, 2.69 g of anhydrous sodium bicarbonate, 3.67 g of4-chloro-p-fluorobutyrophenone ethylene ketal and 55 ml ofdichloromethane is heated at 90° C. (bath temperature) overnight withexclusion of moisture. The cooled mixture is diluted with 80 ml ofdichloromethane and vacuum filtered. The filtrate is concentrated on arotary evaporator and the residual oil is dissolved in 125 ml ofdichloromethane. The solution is washed with 70 ml of 10% sodiumhydroxide solution, 70 ml of water and dried over anhydrous sodiumsulfate. The mixture is vacuum filtered and the filtrate is concentratedto afford an oil which is dissolved in 150 ml of anhydrous ester. Aprecipitate separates and the mixture is filtered through a pad ofanhydrous sodium sulfate. The filtrate is treated with ethereal hydrogenchloride whereupon a viscous gum separates. The gum is dissolved in 7 mlof absolute ethanol and the solution is gradually diluted with 150 ml ofanhydrous ether. Collection of the precipitate by vacuum filtration anddrying affords a crude material. Recrystallization from 400 ml ofisopropanol affords 20.3% of product, mp 253°-254° C. (dec).Concentration of the mother liquor and trituration of the residue with50 ml of hot isopropanol affords an additional 12.4% of product, mp251°-254° C. (dec).

Analysis: Calculated for C₃₁ H₃₄ FNO₂.HCl: 73.27% C; 6.96% H. Found:73.19% C; 7.03% H.

EXAMPLE 34cis-3'-(4-Chlorophenyl)-4-methylaminospiro[cyclohexane-1,1'(3'H)-isobenzofuran]hydrochloride

A stirred suspension of 6.26 g ofcis-3'-(4-chlorophenyl)-4-methylphenoxycarbonylaminospiro[cyclohexane-1,1'(3'H)isobenzofuran],7.85 g of potassium hydroxide pellets, 3.0 ml of water and 35 ml ofn-propanol is heated under reflux for 24 hours. The solution isconcentrated to a syrup, diluted with 150 ml of water and extractedthrice with 50 ml portions of dichloromethane. The organic phase isdried over anhydrous sodium sulfate, filtered and concentrated to anoil. A solution of the oil and 75 ml of anhydrous ether is treated withethereal hydrogen chloride. The precipitate is collected by vacuumfiltration, washed twice with ether and dried over sodium hydroxidepellets in vacuo at 40° C. Recrystallization of the crude product from175 ml of absolute ethanol affords a product, mp 275°-277° C. (dec).Refrigeration of the mother liquor affords a second crop of colorlesscrystalline material, mp 275°-280° C. (dec). Total yield 45.8%.

Analysis: Calculated for C₂₀ H₂₂ ClNO.HCl: 65.94% C; 6.36% H; 3.85% N.Found: 66.13% C; 6;44% H; 3.77% N.

EXAMPLE 35cis-3'-(4-Chlorophenyl)-4-{N-[3-(4-fluorobenzoyl)prop-1-yl]-N-methyl}aminospiro[cyclohexane-1,1'(3'H)-isobenzofuran]hydrochloride

A suspension of 4.07 g ofcis-3'-(4-chlorophenyl)-4-methylaminospiro[cyclohexane-1,1'(3'H)-isobenzofuran]hydrochlorideand 70 ml of methanol is treated with 10 ml of 10% sodium hydroxidesolution. The methanol is removed on a rotary evaporator and the residueis diluted with 100 ml of water and extracted thrice with 70 ml portionsof dichloromethane. The combined organic phase is dried over anhydroussodium sulfate, filtered and concentrated to an oil. A stirredsuspension of the oil, 2.06 g of potassium iodide, 2.08 g of anhydroussodium bicarbonate, 3.06 g of 4-chloro-p-fluorobutyrophenone ethyleneketal and 50 ml of sieve dried dimethylformamide is held at 88°-90° C.(bath temperature) overnight with exclusion of moisture. The cooledmixture is diluted with 100 ml of dichloromethane, vacuum filtered andthe filtrate concentrated at 40°-90° C. on a rotary evaporator. Thesolid residue is diluted with 100 ml of water and extracted with a totalof 200 ml of dichloromethane. The organic phase is washed with 50 ml of10% sodium hydroxide solution, 50 ml of water, dried over anhydroussodium sulfate, vacuum filtered and concentrated to an oil. A solutionof the oil and 100 ml of anhydrous ether is treated with excess etherealhydrogen chloride. A gum separates. A solution of the gum, 70 ml ofmethanol and 40 ml of 3 N hydrochloric acid solution is heated underreflux for 1.5 hours, then allowed to stand overnight at ambienttemperature. The solution is decanted from a small amount of tar and themethanol is evaporated. The residue is made alkaline with 10% sodiumhydroxide solution and extracted with a total of 200 ml ofdichloromethane. The dried(anhydrous sodium sulfate)organic phase isconcentrated to an oil which is dissolved in 300 ml of anhydrous etherand filtered to remove an amorphorous precipitate. The filtrate istreated with ethereal hydrogen chloride and the precipitate is collectedby vacuum filtration and dried to affords a crude material.Recrystallization from 150 ml of acetonitrile affords 18.6% of product,mp 240°-242° C. (dec).

Analysis: Calculated for C₃₀ H₃₁ ClFNO₂.HCl: 68.17% C; 6.12% H; 2.65% N.Found: 67.90% C; 5.97% H; 2.40% N.

EXAMPLE 36cis-4-{N-[3-(4-Fluorobenzoyl)prop-1-yl]-N-methyl}amino-3'-(4-fluorophenyl)spiro[cyclohexane-1,1'(3'H)-isobenzofuran]hydrochloride

A stirred suspension of 4.26 g ofcis-3'-(4-fluorophenyl)-4-methylaminospiro[cyclohexane-1,1'(3'H)-isobenzofuran],2.61 g of potassium iodide, 2.69 g of anhydrous sodium bicarbonate, 3.67g of 2-(3-chloropropyl)-2-(4-fluorophenyl)-1,3-dioxolane and 50 ml ofsieve dried dimethylformamide is held at 90° C. overnight with exclusionof moisture. The cooled mixture is diluted with 60 ml ofdichloromethane, vacuum filtered and concentrated on a rotary evaporatorto an oil. A solution of the oil and 100 ml of dichloromethane is washedwith 100 ml of 10% sodium hydroxide solution, dried over anhydroussodium sulfate, filtered and the filtrate concentrated to an oil. Afiltered solution of the oil and 100 ml of anhydrous ether is treatedwith ethereal hydrogen chloride. The precipitated gum is triturated withfresh ether to afford a yellow powder which is dried at 40° C. oversodium hydroxide pellets. A stirred solution of the crude ketalhydrochloride, 70 ml of methanol and 40 ml of 3 N hydrochloric acid isheated under reflux for 1.5 hours and allowed to stand overnight atambient temperature. The mixture is vacuum filtered and the filtrateconcentrated on a rotary evaporator to remove the methanol. The residueis made alkaline with 10% sodium hydroxide solution and extracted withdichloromethane. The organic phase is washed with water, dried overanhydrous sodium sulfate, filtered and evaporated to an oil. A solutionof the oil and 70 ml of anhydrous ether is filtered through anhydroussodium sulfate and the filtrate is treated with ethereal hydrogenchloride. Recrystallization of the precipitate from 50 ml of 95% ethanolaffords 30% of product, mp 230°-233° C.

Analysis: Calculated for C₃₀ H₃₁ F₂ NO₂.HCl: 70.36% C; 6.31% H; 2.74% N.Found: 70.29% C; 6.35% H; 2.68% N.

EXAMPLE 374-Methylamino-3'-phenylspiro[cyclohexane-1,1'(3'H)-isobenzofuran]hydrochloride

A solution of 7.90 g of4-(ethoxycarbonyl-methylamino)-3'-phenylspiro]cyclohexane-1,1'(3'H)-isobenzofuran]in 50 ml of ethanol and 60 ml of ethylene glycol is refluxed with 10 mlof 50% sodium hydroxide for 20 hours. Ethanol is distilled and themixture is heated for 1 hour at 150° C. After cooling, the mixture isdiluted with 100 ml of water and extracted with ether (3×100 ml). Theethereal solution is washed with water, dried over anhydrous sodiumsulfate, filtered, diluted with 50 ml of ethanol and made acidic with aslight excess of hydrogen chloride/ether. The precipitate is collectedby suction filtration and recrystallized from hydrogen chloride/ether(110 ml/100 ml) to provide 49.3% of product, mp 268°-272° C.

Analysis: Calculated for C₂₀ H₂₃ NO.HCl: 72.82% C; 7.33% H; 10.75% Cl;4.25% N. Found: 72.58% C; 7.16% H; 10.64% Cl; 4.16% N.

EXAMPLE 38cis-4-Dimethylamino-1-{2-[α-methoxy-(phenylmethyl)]phenyl}cyclohexanol

To a cold (-50° C.) stirred solution of 27.7 g of 2-bromobenzhydrylmethyl ether in 50 ml of dry tetrahydrofuran is added dropwise undernitrogen 60 ml of 2.4 M n-butyllithium in hexane. The solution isstirred at -60° C. for 2 hours and a solution of 13.8 g of4-dimethylaminocyclohexanone in 25 ml of dry tetrahydrofuran is addedover 15 minutes at -40° to -50° C. The mixture is stirred at -70° to 0°C. overnight. After addition of 50 ml of water and 50 ml of n-hexane,the mixture is transferred to a separatory funnel and the organic phasewashed with water (3×50 ml), dried over anhydrous sodium sulfate andevaporated to an oil. To the oil is added 300 ml of n-hexane and aftercooling, crystals are collected by suction filtration. Recrystallizationfrom acetone/hexane (25 ml/100 ml) provides 32.4 % of product ascolorless crystals, mp 120°-121° C.

Analysis: Calculated for C₂₂ H₂₉ NO₂ : 77.84% C; 8.61% H; 4.13% N.Found: 78.12% C; 8.64% H; 3.92% N.

EXAMPLE 39cis-4-Dimethylamino-1-[2-(4,6-dihydro-4,4-dimethyl-2-oxazolyl)phenyl]cyclohexanol

A cold (-35° C.) stirrled solution of 25.4 g of2-(2-bromophenyl)-4,4-dimethyloxazoline in 200 ml of dry tetrahydrofuranis treated dropwise under nitrogen with 50 ml of 2.4 M n-butyllithium inhexane. The solution is stirred at -40° to -30° C. for 45 minutes and asolution of 13.9 g of 4-dimethylaminocyclohexanone in 50 ml of drytetrahydrofuran is added dropwise, maintaining the temperature at -40°to -30° C. The mixture is stired overnight at -60° C. to +10° C.,diluted with 500 ml of water and extracted with dichloromethane. Theorganic phase is washed with water, dried over anhydrous sodium sulfateand concentrated to an oil. The oil is stirred with 50 ml of hexane and20 ml of ether to yield a material which is recrystallized fromether/hexane (50 ml/50 ml) to provide 26.1% of product, mp 120°-121.5°C.

Analysis: Calculated for C₁₉ H₂₈ N₂ O₂ : 72.12% C; 8.92% H; 8.85% N.Found: 72.14% C; 8.99% H; 8.94% N.

EXAMPLE 403"-Phenyldispiro[1,3-dioxolane-2,4'-cyclohexane-1',1"(3"H)-isobenzofuran]

To a cooled (-50° C.) stirred solution of 27.7 g of 2-bromobenzhydrylmethyl ether in 80 ml of dry tetrahydrofuran is added dropwise undernitrogen 60 ml of 2.4 M n-butyllithium in hexane. The mixture is stirredfor 2 hours and a solution of 15.9 g of 1,4-dioxaspiro[4.5]decan-8-onein 50 ml of dry tetrahydrofuran is added dropwise, maintaining thetemperature at -40° to -30° C. The mixture is stirred overnight at -70°to +10° C., diluted with 100 ml of water and extracted with 100 ml ofdichloromethane. The organic phase is washed with water (2×50 ml), driedover anhydrous sodium sulfate and concentrated in vacuo. A solution ofthe residue in 400 ml of ethanol is stirred with 50 ml of hydrogenbromide/ether at room temperature for 3 hours. The solvent is removedunder reduced pressure and the remaining oil crystallizes from 100 ml ofmethanol to give 39.6% of product, mp 130°-132° C.

Analysis: Calculated for C₂₁ H₂₂ O₃ : 78.23% C; 6.88% H; Found: 78.09%C; 6.81% H.

EXAMPLE 41 3'-Phenylspiro[cyclohexane-1,1'(3'H)-isobenzofuran]-4-one

A mixture of 3.22 g of3"-phenyldispiro[1,3-dioxolane-2,1'-cyclohexane-4',1"(3"H)-isobenzofuran],350 ml of methanol and 10 ml of 5% hydrochloric acid is stirred at roomtemperature for 4 hours. The solvent is removed under reduced pressureand the residue crystallizes with 50 ml of water, suction filtered,washed with water and dried. Recrystallization from 200 ml of hexaneprovides 71.8% of product, mp 143°-145° C.

Analysis: Calculated for C₁₉ H₁₈ O₂ : 81.99% C; 6.52% H. Found: 82.21%C; 6.64% H.

EXAMPLE 422-[cis-4-(dimethylamino)-1-hydroxycyclohexyl]-α-(4-methylphenyl)benzenemethanol

A solution of 3.68 g of4-dimethylamino-3'-hydroxy-3'-(4-methylphenyl)spiro[cyclohexane-1,1'(3'H)-isobenzofuran]in 50 ml of dry tetrahydrofuran is added dropwise to a suspension of 1.5g of lithium aluminum hydride in 50 ml of dry tetrahydrofuran and themixture is stirred at 50°-60° C. for 1.5 hours, cooled to 10° C.,hydrolyzed with 50 ml of water and diluted with 100 ml of ether. Theorganic phase is washed with water (3×50 ml), dried over anhydroussodium sulfate and concentrated to an oil. The oil is dissolved in 20 mlof ether and diluted with 20 ml of hexane. After cooling overnight (5°C.), the precipitate is collected by filtration to provide 88.6% ofproduct, mp 146°-148° C.

Analysis: Calculated for C₂₂ H₂₉ NO₂ : 77.84% C; 8.61% H; 4.13% N.Found: 77.86% C; 8.65% H; 3.90% N.

EXAMPLE 432-[cis-4-(dimethylamino)-1-hydroxycyclohexyl]-α-methylbenzenemethanol

A solution of 2.74 g ofcis-4-dimethylamino-3'-hydroxy-3'-methylspiro[cyclohexane-1,1'(3'H)-isobenzofuran]in 40 ml of dry tetrahydrofuran is added dropwise to a suspension of 1.5g of lithium aluminum hydride in 50 ml of dry tetrahydrofuran and themixture is stirred at 50°-60° C. for 1.5 hours, cooled to 10° C.,hydrolyzed with 50 ml of water and diluted with 100 ml of ether. Theorganic phase is washed with water (3×50 ml), dried over anhydroussodium sulfate and concentrated to an oil. The oil is dissolved in 10 mlof ether and diluted with 20 ml of hexane. After cooling overnight (5°C.), the crystals are collected by filtration to provide 52.5% ofproduct, mp 147°-148° C.

Analysis: Calculated for C₁₆ H₂₅ NO₂ : 72.97% C; 9.57% H; 5.32% N.Found: 73.11% C; 9.66% H; 5.12% N.

EXAMPLE 44cis-4-(Ethoxycarboxylmethylamino)-3'-phenylspiro[cyclohexane-1,1'(3'H)-isobenzofuran]

To a solution of 15.71 g ofcis-4-dimethylamino-3'-phenylspiro[cyclohexane-1,1'(3'H)-isobenzofuran]in 150 ml of dichloromethane is added at 0° C. 10 ml of ethylchloroformate. The mixture is stirred at room temperature for 1 hour andrefluxed overnight. The solvent is removed under reduced pressure andthe remaining oil extracted with ether (2×500 ml). The extracts arefiltered, the filtrate is made acidic using hydrogen chloride/ether andthe solid is collected. The filtrate is washed with water, dried overanhydrous sodium sulfate and concentrated to an oil which iscrystallized from 50 ml of hexane to give 26.6% of product, mp 96°-98°C.

Analysis: Calculated for C₂₃ H₂₇ NO₃ : 75.59% C; 7.45% H; 3.83% N.Found: 75.84% C; 7.72% H; 3.69% N.

EXAMPLE 45 4-Oximino-3'-phenylspiro[cyclohexane-1,1'(3'H)-isobenzofuran]

A warm solution of 8.35 g of3'-phenylspiro[cyclohexane-1,1'(3'H)-isobenzofuran]-4-one in 300 ml ofethanol is mixed with a solution of 8.16 g of sodium acetate trihydrate,4.17 g of hydroxylamine hydrochloride, and 60 ml of water. The solutionis refluxed for 120 minutes. The solvent is removed in vacuo and theresidue stirred with 300 ml of water. The precipitate is suctionfiltered, washed with water and dried to give 92.3% of product, mp172°-175° C.

Analysis: Calculated for C₁₉ H₁₉ NO₂ : 77.79% C; 6.53% H; 4.77% N.Found: 77.72% C; 6.45% H; 4.61% N.

EXAMPLE 464-Methoximino-3'-phenylspiro[cyclohexane-1,1'(3'H)-isobenzofuran]

A warm solution of 8.35 g of3'-phenylspiro[cyclohexane-1,1'(3'H)-isobenzofuran-4-one] in 300 ml ofethanol is mixed with a solution of 8.16 g of sodium acetate trihydrate,5.01 g of methoxyamine hydrochloride and 80 ml of water. The solution isrefluxed for 3 hours. The solvent is removed in vacuo in a total volumeof 50 ml and to this mixture is added during 1 hour under stirring, 200ml of water. The precipitate is suction filtered, washed with water anddried to give 99.6% of product, mp 137°-147° C.

Analysis: Calculated for C₂₀ H₂₁ NO₂ : 78.15% C; 6.89% H; 4.56% N.Found: 78.09% C; 6.89% H; 4.28% N.

We claim: 1.3"-Phenyldispiro[1,3-dioxolane-2,4'-cyclohexane-1',1"-(3"H)-isobenzofuran].